Corticotropin releasing factor antagonists

ABSTRACT

The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof  
                 
wherein R is aryl or heteroaryl and each of the above groups R may be substituted by 1 to 4 groups selected from: 
             halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —COR 4 , nitro, —NR 3 R 4  cyano, or a group R 5 ;        R 1  is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR 3 R 4  or cyano;    R 2  corresponds to a group CHR 6 R 7 ;    R 3  is hydrogen, C1-C6 alkyl;    R 4  independently from R 3 , has the same meanings;    R 5  is C3-C7 cycloalkyl, which may contain one or more double bonds; aryl; or a 5-6 membered heterocycle; 
           wherein each of the above groups R 5  may be substituted by one or more groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, C1-C6 dialkylamino, nitro or cyano;    
           R 6  is hydrogen, C2-C6 alkenyl or C1-C6 alkyl, wherein each of the above groups R6 may be substituted by one or more groups selected from: C1-C6 alkoxy and hydroxy;    R 7  independently from R 6 , has the same meanings; X is carbon or nitrogen; to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF).

The present invention relates to bicyclic derivatives, to processes fortheir preparation, to pharmaceutical compositions containing them and totheir use in therapy.

The first corticotropin-releasing factor (CRF) was isolated from ovinehypothalami and identified as a 41-amino acid peptide (Vale et al.,Science 213: 1394-1397,1981).

CRF has been found to produce profound alterations in endocrine, nervousand immune system function. CRF is believed to be the majorphysiological regulator of the basal and stress-release ofadrenocorticotropic hormone (“ACTU”), Bendorphin, and otherpro-opiomelanocortin (“POMC”)-derived peptides from the anteriorpituitary (Vale et al., Science 213: 1394-1397,1981).

In addition to its role in stimulating the production of ACTH and POMC,CRF appears to be one of the pivotal central nervous systemneurotransmitters and plays a crucial role in integrating the body'soverall response to stress.

Administration of CRF directly to the brain elicits behavioral,physiological, and endocrine responses identical to those observed foran animal exposed to a stressful environment. Accordingly, clinical datasuggests that CRF receptor antagonists may be useful in the treatment ofthe neuropsychiatric disorders manifesting hypersecretion of CRF, and,in particular, may represent novel antidepressant and/or anxiolyticdrugs.

The first CRF receptor antagonists were peptides (see, e.g., Rivier etal., U.S. Pat. No. 4,605,642; Rivier et al., Science 224: 889, 1984).While these peptides established that CRF receptor antagonists canattenuate the pharmacological responses to CRF, peptide CRF receptorantagonists suffer from the usual drawbacks of peptide therapeuticsincluding lack of stability and limited oral activity. More recently,small molecule CRF receptor antagonists have been reported.

WO 95/10506 describes inter alia compounds of general formula A withgeneral CRF antagonist activity

wherein Y may be CR29; V and Z may be nitrogen and carbon, R3 maycorrespond to an ether derivative and R4 may be taken together with R29to form a 5-membered ring and is —CH(R28) when R29 is —CH(R30).

There is no disclosure related to compounds corresponding to the abovedefinition.

WO 95/33750 also describes compounds of general formula B having CRFantagonistic activity,

in which A and Y may be nitrogen and carbon and B may correspond to anether derivative. There is no disclosure related to compoundscorresponding to the above definition.

Due to the physiological significance of CRF, the development ofbiologically-active small molecules having significant CRF receptorbinding activity and which are capable of antagonizing the CRF receptorremains a desirable goal. Such CRF receptor antagonists would be usefulin the treatment of endocrine, psychiatric and neurologic conditions orillnesses, including stress-related disorders in general.

While significant strides have been made toward achieving CRF regulationthrough administration of CRF receptor antagonists, there remains a needin the art for effective small molecule CRF receptor antagonists. Thereis also a need for pharmaceutical compositions containing such CRFreceptor antagonists, as well as methods relating to the use thereof totreat, for example, stress-related disorders. The present inventionfulfills these needs, and provides other related advantages.

In particular the invention relates to novel compounds which are potentand specific antagonists of corticotropin-releasing factor (CRF)receptors.

The present invention provides compounds of formula (I) includingstereoisomers, prodrugs and pharmaceutically acceptable salts orsolvates thereof

wherein

-   -   R is aryl or heteroaryl and each of the above groups R may be        substituted by 1 to 4 groups selected from:        -   halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6            alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —COR₄, nitro,            —NR₃R₄ cyano, or a group R₅;    -   R₁ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo        C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR₃R₄ or cyano;    -   R₂ corresponds to a group CHR₆R₇;    -   R₃ is hydrogen, C1-C6 alkyl;    -   R₄ independently from R₃, has the same meanings;    -   R₅ is C3-C7 cycloalkyl, which may contain one or more double        bonds; aryl;    -   or a 5-6 membered heterocycle;        -   wherein each of the above groups R₅ may be substituted by            one or more groups selected from: halogen, C1-C6 alkyl,            C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 aynyl,            halo C1-C6 alkoxy, C1-C6 dialkylamino, nitro or cyano;    -   R₆ is hydrogen, C6-C6 alkenyl or C1-C6 alkyl, wherein each of        the above groups R₆ may be substituted by one or more groups        selected from: C1-C6 alkoxy and hydroxy;    -   R₇ independently from R_(6,) has the same meanings;    -   X is carbon or nitrogen.

Acid addition salts of the free base amino compounds of the presentinvention may be prepared by methods well known in the art, and may beformed from organic and inorganic acids. Suitable organic acids includemaleic, malic, fumaric, benzoic, ascorbic, succinic, methanesulfonic,p-toluensulfonic, acetic, oxalic, propionic, tartaric, salicylic,citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic,palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitableinorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric,and nitric acids. Thus, the term “pharmaceutically acceptable salt” ofstructure (I) is intended to encompass any and all acceptable saltforms.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their pharmaceutically acceptable acidaddition salts together with pharmaceutically acceptable solvates.

In addition, prodrugs are also included within the context of thisinvention. Prodrugs are any covalently bonded carriers that release acompound of structure (I) in vivo when such prodrug is administered to apatient. Prodrugs are generally prepared by modifying functional groupsin a way such that the modification is cleaved, either by routinemanipulation or in vivo, yielding the parent compound. Prodrugs include,for example, compounds of this invention wherein hydroxy, amine orsulfhydryl groups are bonded to any group that, when administered to apatient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus,representative examples of prodrugs include (but are not limited to)acetate, formate and benzoate derivatives of alcohol, sulfhydryl andamine functional groups of the compounds of structure (I). Further, inthe case of a carboxylic acid (—COOH), esters may be employed, such asmethyl esters, ethyl esters, and the like.

With regard to stereoisomers, the compounds of structure (I) may havechiral centers and may occur as racemates, racemic mixtures and asindividual enantiomers or diastereomers.

All such isomeric forms are included within the present invention,including mixtures thereof. Furthermore, some of the crystalline formsof the compounds of structure (I) may exist as polymorphs, which areincluded in the present invention.

The term C1-C6 alkyl as used herein as a group or a part of the grouprefers to a linear or branched alkyl group containing from 1 to 6 carbonatoms; examples of such groups include methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tert butyl, pentyl or hexyl.

The term C3-C7 cycloalkyl group means a non aromatic monocyclichydrocarbon ring of 3 to 7 carbon atom such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; whileunsaturated cycloalkyls include cyclopentenyl and cyclohexenyl, and thelike.

The term halogen refers to a fluorine, chlorine, bromine or iodine atom.

The term halo C1-C6 alkyl means an alkyl group having one or more carbonatoms and wherein at least one hydrogen atom is replaced with halogensuch as for example a trifluoromethyl and the like.

The term C2-C6 alkenyl defines straight or branched chain hydrocarbonradicals containing one or more double bond and having from 2 to 6carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl,2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl andthe like.

The term C1-C6 alkoxy group may be a linear or a branched chain alkoxygroup, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy or methylprop-2-oxy and the like.

The term halo C1-C6 alkoxy group may be a C1-C6 alkoxy group as definedbefore substituted with at least one halogen, preferably fluorine, suchas difluoromethoxy, or trifluoromethoxy.

The term C2-C6 alkynyl defines straight or branched chain hydrocarbonradicals containing one or more triple bond and having from 2 to 6carbon atoms including acetylenyl, propynyl, 1-butynyl, 1-pentynyl,3-methyl-1-butynyl and the like.

The term aryl means an aromatic carbocyclic moiety such as phenyl,biphenyl or naphthyl.

The term heteroaryl means an aromatic heterocycle ring of 5- to 10members and having at least one heteroatom selected from nitrogen,oxygen and sulfur, and containing at least 1 carbon atom, including bothmono-and bicyclic ring systems.

Representative heteroaryls include (but are not limited to) furyl,benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl,isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl,isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, triazolyl, tetrazolyl,and quinazolinyl.

The term 5-6 membered heterocycle means, according to the abovedefinition, a monocyclic heterocyclic ring which is either saturated,unsaturated or aromatic, and which contains from 1 to 4 heteroatomsindependently selected from nitrogen, oxygen and sulfur, and wherein thenitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen heteroatom may be optionally quaternized. The heterocycle maybe attached via any heteroatom or carbon atom. Thus, the term include(but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl,piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

Thus, representative compounds of this invention include the followingstructure (I) and (I), depending upon the meaning of X according to thedefinition of compounds (I) given above, and in which R, R₁ and R₂ aredefined as before:

Compounds of formula (Ia) are particularly preferred.

Even more preferred embodiments of the invention include, but are notlimited to, compounds of the formula (I), (Ia), and (Ib): wherein:

-   -   R₁ is C1-3 alkyl or halo C1-C3 alkyl, preferably methyl or        trifluoromethyl;    -   R is an aryl group selected from: 2,4-dichlorophenyl,        2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethyl,        2-chloro-4-methoxyphenyl, 2,4-dimethylphenyl,        2-methyl-4-methoxyphenyl, 2-methyl-4-chlorophenyl,        2-methyl-4-trifluoromethyl, 2,4-dimethoxyphenyl,        2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-chlorophenyl,        3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl,        2-methoxy isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl,        2-methoxy-4-isopropylphenyl, 2-methoxy-4-methylphenyl,        2-trifluoromethyl-4-chlorophenyl, 2,4-trifluoromethylphenyl,        2-trifluoromethyl-4-methylphenyl,        2-trifluoromethyl-4-methoxyphenyl, 2-bromo isopropylphenyl,        4-methyl-6-dimethylaminopyridin-3-yl,        4-dimethylamino-6-methylpyridin-3-yl,        6-dimethylamino-pyridin-3-yl and 4-dimethylaminopyridin-3-yl.

Preferred compounds according to the invention are:

-   7-(2,4    chlorophenyl)-4-(1-ethyl-propoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]-pyrimidine    (1-1);-   7-(2,4-dichlorophenyl)-4-(1-isopropyl-2-methyl-propoxy)-2-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d]pyrimidine    (1-2);-   7-(2,4-dichlorophenyl)-4-(1-isopropyl-3-methyl-butoxy)-2-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d]pyrimidine    (1-3);-   7-(2,4-dichlorophenyl)-4-(2-methoxy-1-methoxymethyl-ethoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine    (1-1-4);-   7-(2,4-dichlorophenyl)-4-(2-ethyl-butoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]-pyrimidine    (1-5);-   7-(2,4-dichlorophenyl)-4-(2-ethoxy-1-ethoxymethyl-ethoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine    (1-6);-   7-(2,4-bis-trifluoromethyl-phenyl)-4-(1-ethyl-propoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine    (1-7);-   7-(2,4-dichlorophenyl)4-(1-ethyl-2-methyl-allyloxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine    (1-8);-   7-(2,4-dichlorophenyl)4-(1-methoxymethyl-propoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine    (1-9);-   2-[7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yloxy]butan-1-ol    (1-10);-   7-(2,4-bis-trifluoromethyl-phenyl)-4-(1-methoxymethyl-propoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine    (1-12);-   4-[4-(1-ethyl-propoxy)-2-methyl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-trifluoromethyl-benzamide    (1-13);-   4-(1-ethyl-propoxy)-7-[2-(1-ethyl-propoxy)-6-trifluoromethyl-pyridin-3-yl]-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine    (1-14);-   2-[4-(1-ethyl-propoxy)-2-methyl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-5-trifluoromethyl-benzonitrile    (1-15).

In general, the compounds of structure (I) may be made according to theorganic synthesis techniques known to those skilled in this field, aswell as by the representative methods set forth in the Examples.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R, R₁, R₂, R₃, R₄, R₅, R₆, R₇ X and n have themeaning as previously defined for compounds of formula (I) unlessotherwise stated.

Compounds of formula (I), may be prepared by reaction of a compound offormula (m)

wherein L is a leaving group, preferably an halogen group (e.g.chlorine) with the alcohol compound (III)HOCHR_(2a)R_(3a)  (III)wherein R_(2a) and R_(3a) have the meanings defined above for R₂ and R₃or are a group convertible thereto.The reaction can be optionally carried out in an aprotic solvent such asN,N-dimethylformamide in the presence of a strong base such as sodiumhydride and with heating. For the preparation of the compounds offormula (I), wherein R₃ and/or R₂ are/is hydroxy, the reaction isconveniently carried out using an intermediate of formula (I) in whichR_(3a) and/or R_(2a) are/is a protected hydroxyl group.

When the group R_(3a) and/or R_(2a) are/is a protected hydroxyl groupthis is conveniently an ether or an acyloxy group. Examples of suitableethers include trityl ether, hydrocarbylsilyl group such astrialkylsilyl e.g. trimethylsilyl or t-butyldimethylsilyl. When theprotected hydroxyl group represents an acyloxy group, examples ofsuitable groups include alkanoyl e.g. acetyl, pivaloyl; alkenoyl e.g.allylcarbonyl; aroyl e.g. pnitrobenzoyl; alkoxycarbonyl e.g.t-butoxycarbonyl.

Compounds of formula (IIa), equivalent to compounds of formula (II) inwhich X is nitrogen, may be prepared by cyclisation of a compound offormula (IV).

The cyclisation takes place in an aprotic solvent such astetrahydrofuran and in the presence of a tertiary amine such as triethylamine and mesyl chloride.

Compounds of formula (IV) may be prepared by oxidation of a compound offormula (V)

wherein R_(a) is a suitable nitrogen protecting group, to thecorresponding aldehyde followed by reduction to alcohol and removal ofthe nitrogen protecting group.

The oxidation is carried out with ozone at low temperature, e.g. −78°C., in a solvent such as dichloromethane.

The reduction takes places using for example sodium borohydride in asolvent such as alcohol.

Examples of suitable nitrogen protecting group include alkoxycarbonyl,e.g. t-butoxycarbonyl and arylsulphonyl, e.g phenylsulphonyl.

Compounds of formula (V) may be prepared by reaction of a compound offormula (VI), wherein L is defined as above, with amine (VII).

The reaction preferably takes place in an aprotic solvent such astetrahydrofuran, dichlorometane or N,N-dimethyl formamide in thepresence of a strong base such sodium hydride and with heating.

Compounds of formula (VI) and (VII) are either known compounds or may beprepared by analogous method to those described for known compounds.

Compounds of formula (IIb), equivalent to compounds of formula (II) inwhich X is a carbon atom, may be prepared by conversion of the hydroxygroup of compounds of formula (VIII into a leaving group.

For example, the halogenation reaction may be carried out usingconventional methods known in the art Thus, e.g. the reaction may becarried out by treatment with PO(Hal)₃, wherein Hal is preferablychlorine.

Compounds of formula (VIII) may be prepared by cyclisation of a compoundof formula (X) with a salt (e.g. hydrochloride) of acetamidine (IX).

The reaction is carried out in the presence of an alkaline organic baseC₁-C₄ (e.g. sodium methoxide) in a solvent such as methyl alcohol.

Compounds of formula (X) may be prepared by cyclisation of a compound offormula (XI), in which R₈ is a linear or branched C1-C4 alkyl and p isdefined as above.

The cyclisation may be carried out in the presence of an organicalkaline C1-C4 alkoxyde (e.g sodium methoxide) in an aprotic solventsuch as N,N-dimethylformamide or toluene and at temperature ranging from20° to 100° C.

Compounds of formula (XI) can be prepared by reaction of a compound offormula (XII) with a compound of formula (XIII), wherein L is preferablya bromine or iodine atom.

The reaction is carried out in aprotic solvent such as an ether e.g.tetrahydrofuran at low temperature, e.g. −78° C., and in the presence ofa strong base such as Lithium diisopropylamide.

Alternatively, compounds of formula (X) may be prepared according to thefollowing scheme from 2-chloro-cyclopentanone, by reaction with asuitable Grignard derivative of the group R and then carboxymethylatedas described above.

In any of the above reaction the nitrogen protecting group and hydroxylprotecting group may be removed by conventional procedures known forremoving such groups (such as those described in Protective Groups inOrganic Chemistry, pages 46-119, Edited by J F W McOmie (Plenum Press,1973)).

Thus, when R_(a) is alkoxycarbonyl, the group may be removed by acidhydrolisis using for example trifluoro acetic acid.

When, for example, the hydoxyl protecting group is a trityl ether, thegroup may be removed by acid hydrolisis using for example trifluoroacetic acid.

Pharmaceutical acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisation or evaporation of an appropriatesolvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods. Thus the required enantiomer may be obtained fromthe racemic compound of formula (I) by use of chiral HPLC procedure.

The invention as herein described also includes isotopically-labeledcompounds, which are identical to those falling within the scope offormulas I, Ia and Ib, but for the fact that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine, iodine, and chlorine, such as ³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵ICompounds of the present invention and pharmaceutically acceptable saltsof said compounds that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ⁸Fisotopes are particularly useful in PET (positron emission tomography),and ¹²⁵I isotopes are particularly useful in SPECT (single photonemission computerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of this invention can generally beprepared by carrying out the procedures disclosed in the Schemes and/orin the Examples below, by substituting a readily available isotopicallylabeled reagent for a non-isotopically labeled reagent.

In another aspect of the present invention, the compounds of formula (I)in which R₂ represents —CBR₆R₇, wherein R₆ or R₇ are defined as beforeand are substitueted by an isotopically labeled C1-6 alkoxy group,preferably an isotopically labeled methoxy group, may be very useful forthe scope outlined before.

In particular, the compounds (1-9) and (1-12), whose preparation isreported in Example 1, show a good activity and may be easily preparedin a radiolabeled form as described above. These radiolabeled compoundsmay be easily prepared according to the following process, starting fromthe hydroxy precursors.

According to this process, the hydroxy precursors of radiolabeledcompounds (1-9a) and (1-12a), compounds (1-10) and (1-16) described inExample 1 are methylated with ¹¹CH₃I, following the procedure describedin Examples 4 and 5.

The CRF receptor antagonists of the present invention demonstrateactivity at the CRF receptor site including CRF 1 and CRF 2 receptorsand may be used in the treatment of conditions mediated by CRF or CRFreceptors.

The effectiveness of a compound as a CRF receptor antagonist may bedetermined by various assay methods. Suitable CRF antagonists of thisinvention are capable of inhibiting the specific binding of CRF to itsreceptor and antagonizing activities associated with CRF. A compound ofstructure (I) may be assessed for activity as a CRF antagonist by one ormore generally accepted assays for this purpose, including (but notlimited to) the assays disclosed by DeSouza et al. (J. Neuroscience 7:88,1987) and Battaglia et al. (Synapse 1: 572,1987).

The CRF receptors-binding assay was performed by using the homogeneoustechnique of scintillation proximity (SPA). The ligand binds torecombinant membrane preparation expressing the CRF receptors which inturn bind to wheat germ agglutinin coated SPA beads. In the ExperimentalPart will be disclosed the details of the experiments.

With reference to CRF receptor binding affinities, CRF receptorantagonists of this invention have a Ki less than 10 μm.

In a preferred embodiment of this invention, a CRF receptor antagonisthas a Ki less than 1 μm.

In a more preferred embodiment the value of Ki is less than 0.1 μM andmore preferably less than 0.01 μm. As set forth in greater detail below,the Ki values of representative compounds of this invention were assayedby the methods set forth in Example 2.

Preferred compounds having a Ki of less than 1 μm are compound numbers1-5,1-6, and 1-14.

More preferred compounds having a Ki less than 0.1 μm are compoundnumbers 1-2, 1-4, 1-8,1-10,1-13 and 1-15.

Even more preferred compounds having a Ki less than 0.1 μm are compoundnumbers 1-1,1-3, 1-7,1-9 and 1-12.

Compounds of the invention are useful in the treatment of centralnervous system disorders where CRF receptors are involved. In particularin the treatment or prevention of major depressive disorders includingbipolar depression, unipolar depression, single or recurrent majordepressive episodes with or without psychotic features, catatonicfeatures, melancholic features, atypical features or postpartum onset,the treatment of anxiety and the treatment of panic disorders. Othermood disorders encompassed within the term major depressive disordersinclude dysthymic disorder with early or late onset and with or withoutatypical features, neurotic depression, post traumatic stress disordersand social phobia; dementia of the Alzheimer's type, with early or lateonset, with depressed mood; vascular dementia with depressed mood; mooddisorders induced by alcohol, amphetamines, cocaine, hallucinogens,inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics andother substances; schizoaffective disorder of the depressed type; andadjustment disorder with depressed mood. Major depressive disorders mayalso result from a general medical condition including, but not limitedto, myocardial infarction, diabetes, miscarriage or abortion, etc.

Compounds of the invention are useful as analgesics. In particular theyare useful in the treatment of traumatic pain such as postoperativepain; traumatic avulsion pain such as brachial plexus; chronic pain suchas arthritic pain such as occurring in osteo-, rheumatoid or psoriaticarthritis; neuropathic pain such as post-herpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia,peripheral neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, AIDS related neuropathy, occipital neuralgia, geniculateneuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,phantom limb pain; various forms of headache such as migraine, acute orchronic tension headache, temporomandibular pain, maxillary sinus pain,cluster headache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapment pain; sport's injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar pain;itch; and thalamic pain such as post stroke thalamic pain.

Compounds of the invention are also useful for the treatment ofdysfunction of appetite and food intake and in circumstances such asanorexia, anorexia nervosa and bulimia.

Compounds of the invention are also useful in the treatment of sleepdisorders including dysomnia, insomnia, sleep apnea, narcolepsy, andcircadian ritmic disorders.

Compounds of the invention are also useful in the treatment orprevention of cognitive disorders. Cognitive disorders include dementia,amnestic disorders and cognitive disorders not otherwise specified.

Furthermore compounds of the invention are also useful as memory and/orcognition enhancers in healthy humans with no cognitive and/or memorydeficit.

Compounds of the invention are also useful in the treatment of toleranceto and dependence on a number of substances. For example, they areuseful in the treatment of dependence on nicotine, alcohol, caffeine,phencyclidine (phencyclidine like compounds), or in the treatment oftolerance to and dependence on opiates (e.g. cannabis, heroin, morphine)or benzodiazepines; in the treatment of cocaine, sedative ipnotic,amphetamine or amphetamine-related drugs (e.g. dextroamphetamine,methylamphetamine) addiction or a combination thereof.

Compounds of the invention are also useful as anti-inflammatory agents.In particular they are useful in the treatment of inflammation inasthma, influenza, chronic bronchitis and rheumatoid arthritis; in thetreatment of inflammatory diseases of the gastrointestinal tract such asCrohn's disease, ulcerative colitis, inflammatory bowel disease (IBD)and non-steroidal anti-inflammatory drug induced damage; inflammatorydiseases of the skin such as herpes and eczema; inflammatory diseases ofthe bladder such as cystitis and urge incontinence; and eye and dentalinflammation.

Compounds of the invention are also useful in the treatment of allergicdisorders, in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of the invention are also useful in the treatment of emesis,i.e. nausea, retching and vomiting. Emesis includes acute emesis,delayed emesis and anticipatory emesis. The compounds of the inventionare useful in the treatment of emesis however induced. For example,emesis may be induced by drugs such as cancer chemotherapeutic agentssuch as alkylating agents, e.g. cyclophosphamide, carmustine, lomustineand chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin,mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine,methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide,vinblastine and vincristine; and others such as cisplatin, dacarbazine,procarbazine and hydroxyurea; and combinations thereof; radiationsickness; radiation therapy, e.g. irradiation of the thorax or abdomen,such as in the treatment of cancer; poisons; toxins such as toxinscaused by metabolic disorders or by infection, e.g. gastritis, orreleased during bacterial or viral gastrointestinal infection;pregnancy; vestibular disorders, such as motion sickness, vertigo,dizziness and Meniere's disease; post-operative sickness;gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine; andgastro-oesophageal reflux disease, acid indigestion, over-indulgence offood or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn and dyspepsia.

Compounds of the invention are of particular use in the treatment ofgastrointestinal disorders such as irritable bowel syndrome (IBS); skindisorders such as psoriasis, pruritis and sunburn; vasospastic diseasessuch as angina, vascular headache and Reynaud's disease; cerebralischeamia such as cerebral vasospasm following subarachnoid haemorrhage;fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders related to immune enhancement or suppressionsuch as systemic lupus erythematosus and rheumatic diseases such asfibrositis; and cough.

Compounds of the invention are useful for the treatment of neurotoxicinjury which follows cerebral stroke, thromboembolic stroke, hemorrhagicstroke, cerebral ischemia, cerebral vasospam, hypoglycemia, hypoxia,anoxia, perinatal asphyxia cardiac arrest.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the preparation of a medicament for use in the treatment ofconditions mediated by CRF.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofcondition mediated by CRF, comprising administration of an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt or a solvate thereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.

Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

A proposed dose of the compounds of the invention is 1 to about 1000 mgper day. It will be appreciated that it may be necessary to make routinevariations to the dosage, depending on the age and condition of thepatient and the precise dosage will be ultimately at the discretion ofthe attendant physician or veterinarian. The dosage will also depend onthe route of administration and the particular compound selected.

Thus for parenteral administration a daily dose will typically be in therange of 1 to about 100 mg, preferably 1 to 80 mg per day. For oraladministration a daily dose will typically be within the range 1 to 300mg e.g. 1 to 100 mg.

EXAMPLES

In the Intermediates and Examples unless otherwise stated:

Melting points (m.p.) were determined on a Gallenkamp m.p. apparatus andare uncorrected. All temperatures refers to ° C. Infrared spectra weremeasured on a FT-IR instrument. Proton Magnetic Resonance (¹H-NMR)spectra were recorded at 400 MHz, chemical shifts are reported in ppmdownfield (d) from Me₄Si, used as internal standard, and are assigned assinglets (s), doublets (d), doublets of doublets (dd), triplets (t),quartets (q) or multiplets (m). Column chromathography was carried outover silica gel (Merck AG Darmstaadt, Germany). The followingabbreviations are used in text: EtOAc=ethyl acetate, cHex=cyclohexane,CH₂Cl₂=dichloromethane, Et₂O=dietyl ether, DMF═N,N′-dimethylformamide,DIPEA=N,N-diisopropylethylamine MeOH=methanol, Et₃N=triethylamine,TFA=trifluoroacetic acid, THF=tetrahydrofuran,DIBAL-H=diisobutylaluminium hydride, DMAP=dimethylaminopyridine,LHMDS=lithiumhexamethyldisilazane; Tlc refers to thin layerchromatography on silica plates, and dried refers to a solution driedover anhydrous sodium sulphate; r.t. (RT) refers to room temperature.

Intermediate 1

5-Allyl-4,6-dihydroxy-2-methyl-pyrimidine

Sodium (2 g) was added portionwise to anh. MeOH (100 ml), at 0° C.,under N₂. After consumption of metallic sodium, acetamidinehydrochloride (8.4 g) was added. After 10 min. of stirring theprecipitated NaCl was filtered off. Diethyl-allyl-malonate (6 ml) wasadded to the solution of free acetamidine and the mixture was stirred atr.t. for 2 days. The reaction mixture was concentrated and thenneutralized with concentrated hydrochloric acid, filtered to obtain thetitle compound as a white solid (4.25 g).

NMR (¹H, DMSO-d₆): δ 11.61 (bs, 2H), 5.75 (m, 1H), 4.92 (m, 1H), 4.84(m, 1H), 2.94 (d, 2H), 2.19 (s, 3H).

MS (m/z): 166 [M]⁺.

Intermediate 2

5-Allyl-4,6-dichloro-2-methyl-pyrimidine

Intermediate 1 (6.0 g) was mixed with POCl₃ (70 ml) and heated at refluxfor 3 hr. The resulting solution was cooled to r.t. and poured slowlyinto ice/water (600 ml) with vigorous stirring. The product wasextracted with EtOAc (3×50 ml). The combined organic extracts werewashed with saturated NaHCO₃ (60 ml) and brine (40 ml), dried overNa₂SO₄, filtered and concentrated in vacuo. The crude oil was purifiedby flash chromatography (silica gel, cHex 100%). The title compound wasobtained as a light yellow oil (4.78 g).

NMR (¹H, CDCl₃): δ 5.85 (m, 1H), 5.15 (dq, 1H), 5.11 (dq, 1H), 3.61 (dt,2H), 2.67 (s, 3H).

MS (m/z): 202 [M]⁺0.2Cl; 167 [MH-Cl]⁺, 1 Cl.

Intermediate 3

(5-Allyl-6-chloro-2-methyl-pyrimidin-4-yl)-(2,4-dichloro-phenyl)-amine

A solution of 2,4-dichloroaniline (798 mg) in anh. ThF (22 ml), underN₂, was treated with sodium hydride (95% in mineral oil, 393 mg) at 0°C. for 15 min before intermediate 2 (1 g) was added. The mixture washeated at reflux for 3 hr and quenched with water (20 ml). The productwas extracted with ethyl acetate (2×20 ml), dried over Na₂SO₄ andconcentrated in vacuo. The crude product was purified by flashchromatography (silica gel, EtOAc/cHex 4/96) to give the title compoundas a white solid (725 mg).

NMR (¹H, CDCl₃): δ 8.52 (d, 1H), 7.40 (d, 1H), 7.27 (dd, 1H), 7.21 (bs,1H), 5.90 (m, 1H), 5.26 (m, 2H), 3.58 (m, 2H), 2.57 (s, 3H).

MS (m/z): 327 [M]⁺, 3Cl.

Intermediate 4

(5-Allyl-6-chloro-2-methyl-pyrimidin-4yl)2,4dichloro-phenyl) carbamicacid tert-butyl ester

To a solution of intermediate 3 (146 mg) in anh. CH₂Cl₂ (11 ml), underN₂, was added (Boc)₂O (194 mg) and DMAP (cat). The reaction mixture wasstirred at r.t. for 18 hr. The solution was diluted with water (10 ml)and extracted with EtOAc (3×15 ml). The combined organic extracts weredried over anh. Na₂SO₄, filtered and concentrated to dryness in vacuo.Flash chromatography of the crude product (silica gel, cHex/EtOAc 95:5)gave the title compound as colourless oil (164 mg)

NMR (¹H, CDCl₃): δ 7.47 (d, 1H), 7.20 (dd, 1H), 7.17 (d, 1H), 5.75 (tq,1H), 5.05(dd, 1H), 4.97 (dd, 1H), 3.52 (d, 2H), 2.58 (s, 3H), 1.44 (s,9H).

IR (nujol, cm⁻¹): 1729.

MS (m/z): 428 [MH]⁺, 3Cl; 372 [MH-tBu+H]⁺, 328 [H-Boc+H]⁺

Intermediate 5

[6-Chloro-5-(2-hydroxy-ethyl-2-methyl-pyrimidinyl-4-yl]-(2,4chloro-phenyl)carbamicacid tert-butyl ester

A solution of intermediate 4 (160 mg) in CH₂Cl₂ (9 ml) and CH₃OH (1 ml)was ozonized (5 g.h7′) at −78° C. for 10 min. When all the allylpyrimidine had disappeared (according to tlc), the reaction mixture wasfirst flushed with oxygen and then with nitrogen for 20 min. To thecooled reaction mixture was added NaBH₄ (56 mg) and the temperature wasallowed to warm up to r.t. The solution was stirred for 3 hr at r.t. Itwas then diluted with water (10 ml) and extracted with CH₂Cl₂ (3×10 ml).The combined organic extracts were dried over anh. Na₂SO₄, filtered andconcentrated to dryness in vacuo. The crude product was purified byflash chromatography (silica gel, cHex/EtOAc 85:15) to give the titlecompound as white solid (120 mg).

NMR (¹H, CDCl₃): δ 7.49 (d, 1H), 7.37 (d, 1H), 7.23 (dd, 1H), 3.93 (q,2H), 3.05 (t, 2H), 2.59 (s, 3H), 1.89 (bs, 1H), 1.45 (s, 9H).

IR (nujol, cm⁴): 3430,1717.

MS (m/z): 432 [MH]⁺, 3Cl; 454 [MH+Na]⁺, 332 [MH-Boc+H]⁺

Intermediate 6

Methanesulfonic acid 2-{4-tert-butoxcarbonyl(2.4-dichloro-phenylamino]-6-chloro-2-methyl-pyrimidin-5-yl} ethyl ester

To a solution of intermediate 5 (337 mg) in anh. CH₂Cl₂ (15 ml), at r.t,under N₂, was added Et₃N (5451 μl) and CH₃SO₂Cl (120 μl). The reactionwas stirred at r.t. for 18 hr. Water (15 ml) and EtOAc (15 ml) wereadded, the phases were separated and the aqueous layer was extractedwith additional EtOAc (2×15 ml). The combined organic extracts werewashed with H₂O (20 ml), dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by flash chromatography (silicagel, cHex/EtOAc 75:25) to give the title compound as a white foam (327mg).

NMR (¹H, CDCl₃): δ 7.49 (d, 1H), 7.34 (d, 1H), 7.26 (m, 1H), 4.52 (t,2H), 3.24 (t, 2H), 2.98 (s, 3H), 2.58 (s, 3H), 1.45 (s, 9H).

MS (m/z): 510 [MH]⁺, 3Cl; 532 [MH+Na]⁺, 454 [MH−tBu+H]⁺, 410 [MH−Boc+H]⁺

Intermediate 7

Methanesulfonic acid2-[4-chloro-6(2,4-dichloro-phenylamino)-2-methyl-pyrimidin-5-yl]-ethylester

A solution of intermediate 6 (327 mg) in 20% TFA in CH₂Cl₂ (10 ml) wasstirred at r.t. for 2 hr. The solvent was removed in vacuo and theresidue was partitionned between EtOAc (10 ml) and sat. aq. NaHCO₃ (10ml), and the layers were separated. The aqueous layer was extracted withEtOAc (3×10 ml), and the combined organic extracts were dried overNa₂SO₄, filtered and concentrated to dryness in vacuo to dobtain thetitle compound as white solid (224 mg).

NMR (¹H, CDCl₃): δ 8.39 (d, 1H), 7.49 (d, 1H), 7.44 (bs, 1H), 7.34 (dd,1H), 4.56 (t, 2H), 3.28 (t, 2H), 3.03 (s, 3H), 2.61 (s, 3H).

MS (m/z): 410 [MH]⁺, 3Cl.

Intermediate 8

4-Chloro-7-(2,4-dichloro-phenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

To a solution of intermediate 7 (224 m) in anh. TBF (10 ml) was added,at r.t., under N₂, 40 NaH (95% mineral oil, 20 mg). The reaction wasstirred for 2 hr at r.t. The solution was diluted with water (10 ml) andextracted with EtoAc (2×15 ml). The combined organic extracts were driedover anh. Na₂SO₄, filtered and concentrated to dryness in vacuo. Thecrude product was purified by flash chromatography (silica gel,cHex/EtOAc 75:25) to give the title compound as a white solid (158 mg).

NMR (¹H, CDCl₃): δ 7.51 (s, 1H), 7.33 (m, 2H), 4.04 (t, 2H), 3.21 (t,2H), 2.44 (s, 3M).

MS (m/z): 313[MH]⁺, 3Cl

Intermediate 9

(5-Allyl-6-chloro-2-methyl-pyrimidin-4-yl)2,4-bis-trifluoromethyl-phenyl)-amine

A solution of 2,4-bis-trifluoromethyl-aniline (563 mg) in anh. ThF (4ml), at r.t., under N₂, was treated with sodium hydride (80% in mineraloil, 111 mg) at 0° C. for 15 min. Intermediate 2 (500 mg) was thenadded. The mixture was heated to reflux for 3 hr and quenched with water(10 ml). The aqueous layer was extracted with EtOAc (3×15 ml). Thecombined organic extracts were dried over Na₂SO₄, the solids werefiltered and the solvent evaporated in vacuo. The crude product waspurified by flash chromatography (silica gel, EtOAc/cHex 4:96) to givethe title compound as a brown oil (260 mg).

NMR (¹H, CDCl₃): δ 8.55 (d, 1H), 7.88 (bs, 1H), 7.83 (bd, 1H), 7.19 (bs,1H), 5.92 (m, 1H), 5.27 (m, 1H), 5.17 (m, 1H), 3.56 (m, 2H), 2.58 (s,3H).

MS (m/z): 396 [MH]⁺.

Intermediate 10

(5-Allyl-6-chloro-2-methyl-pyriridin-4-yl)-(2,4-bis-trifluorometh l-abenl) carbamic acid tert-butyl ester

To a solution of intermediate 9 (435 mg) in anh. CH₂Cl₂ (3 ml), underN₂, at r.t., was added (Boc)₂O (336 mg) and DMAP (cat). The reaction wasstirred at r.t. for 40 hr. The solution was diluted with water (10 ml)and extracted with EtOAc acetate (3×15 ml). The combined organicextracts were dried over anh. Na₂SO₄, the solids were filtered and thesolvent was evaporated to dryness in vacuo. Flash chromatography of thecrude product (silica gel, cHex/EtOAc 96:4) gave the title compound as ayellow oil (460 mg)

NMR (¹H, CDCl₃): δ 7.96 (s, 1 H), 7.83 (d, 1H), 7.55 (d, 1H), 5.90 (m,1H), 5.18 (dd, 1H), 5.13 (d, 1H), 3.56 (m, 2H), 2.50 (s, 3H), 1.41 (s,9H).

IR (nujol, cm⁻¹): 1726.

MS (m/z): 496 [H]⁺; 440 [MH-tBu+H]⁺; 396 [MH-BOC+H]⁺.

Intermediate 11

(2,4-Bis-trfuoromethyl-phenyl)-[6-chloro-5-(2-hydroxy-ethyl)-2-methyl-pyrimidin-4-yl]-carbamicacid tert-butyl ester

A solution of intermediate 10 (460 mg) in anh. CH₂Cl₂ (9 ml) and CH₃OH(1 ml) was ozonized (5 g.h⁻¹) at −78° C. for 20 min. When all thestarting material had disappeared (according to tlc in cHex/EtOAc 7:3),the reaction mixture was first flushed with oxygen and then withnitrogen for 5 min. To the cooled reaction mixture was added NABH₄ (137mg) and the temperature was allowed to warm up to r.t. The solution wasstirred for 1.5 hr at r.t. It was then diluted with water (10 ml) andextracted with CH₂Cl₂ (3×10 ml). The combined organic extracts weredried over anh. Na₂SO₄, the solids were filtered and the solventevaporated to dryness in vacuo. The crude product was purified by flashchromatography (silica gel, cHex/EtOAc 9:1) to give the title compoundas white solid (385 mg).

NMR (¹H, CDCl₃): δ 7.96 (bs, 1H), 7.86 (bd, 1H), 7.74 (d, 1H), 4.13-4.05(m, 2H), 3.07 (td, 2H), 2.49 (s, 3H), 2.21 (bs, 1H), 1.41 (s, 9H).

IR (nujol, cm¹): 1724, 1602.

MS (m/z): 500 [MH]⁺; 444 [MH−tBu+H]⁺; 400 [MH−Boc+H]⁺.

Intermediate 12

Methanesulfonic acid2-[4-(2,4-bis-trifluoromethyl-phenylamino)-6-chloro-2-methyl-pyrimidin-5-yl]-ethylester

To a solution of intermediate 11 (385 mg) in anh. CH₂Cl₂ (5 ml), at r.t,under N₂, were added Et₃N (540 μl) and CH₃SO₂Cl (120 μl). The reactionmixture was stirred at r.t. for 18 hr. Water (15 ml) and CH₂Cl₂ (15 ml)were added and the phases were separated. The aqueous layer wasextracted with CH₂Cl₂ (2×15 ml). The combined organic extracts weredried over Na₂SO₄, the solids filtered and the solvent evaporated invacuo.

A solution of the crude product in 20% TFA/CH₂Cl₂ (4 ml) was stirred atr.t. for 2 hr. The solvent was removed in vacuo and the residue wasredissolved in EtOAc (10 ml) and sat. aq. NaHCO₃ (10 ml). The phaseswere separated and the aqueous layer was extracted EtOAc (3×10 ml). Thecombined organic extracts were dried over Na₂SO₄, the solids werefiltered and the solvent evaporated to dryness in vacuo to deliver thetitle compound as a yellow solid (322 mg).

NMR (¹H, CDCl₃): δ 9.09 (bs, 1H), 8.12 (d, 1H), 8.09 (s, 1H), 7.74 (d,1H), 4.36 (t, 2H), 3.23 (t, 2H), 3.15 (s, 3H), 2.19 (s, 3H).

IR (CDCl₃, cm⁻¹): 1346, 1177

MS (m/z): 478[MH]⁺.

Intermediate 13

7-(2,4-Bis-trifluoromethyl-phenyl)-4chloro-2-methyl-6,7-dihydro-5H-pvrrolo[2,3-d]pyrimidine

To a solution of intermediate 12 (320 mg) in anh. TBF (8 ml) was added,at r.t., under N₂, NaH (80% mineral oil, 30 mg). The reaction mixturewas stirred for 2 hr at 60° C. It was then diluted with water (10 ml)and extracted with EtOAc (2×15 ml). The combined organic extracts weredried over anh. Na₂SO₄, the solids were filtered and the solventevaporated to dryness in vacuo. The crude product was purified by flashchromatography (silica gel, cHex/EtOAc 90:10) to give the title compoundas a white solid (154 mg).

Alternatively, intermediate 13 can be prepared from intermediate 24 asfollows:

To a solution of intermediate 24 (514 mg, 1.29 mmol) in anh. CH₂Cl₂ (20mL), at 0° C., under N₂, were added Et₃N (712 μL, 4 eq)) and mesylchloride (197 μL, 2 eq) and the reaction mixture was stirred at r.t. for18 hr. Water (20 mL) was then added and the phases were separated. Theaqueous layer was extracted with CH₂Cl₂ (2×20 mL) and the combinedorganic extracts were dried over anh. Na₂SO₄. The solids were filteredand the solvent was evaporated. The crude product was purified by flashchromatography (silica gel, 8:2 cHex/EtOAc) to give the title compoundas a white solid (430 mg, 87%).

NMR (¹H, CDCl₃): δ 8.04 (s, 1H), 7.93 (s, 1H), 7.53 (d, 1H), 4.00 (t,2H), 3.24 (t, 2H), 2.42 (s, 3H).

MS (m/z): 381[MH]⁺, 1Cl.

Intermediate 14

1,3-Dimethoxy-propan-2-ol

Metallic sodium (626 mg) was dissolved in anh. MeOH (7 mL), at 0° C.,under N₂. When the solution was ready, 1,3-dichloro-propan-2-ol (1 mL)was added dropwise. NaCl precipitated immediately, and an additionalportion of anh. MeOH (3 mL) was added and the reaction mixture washeated at reflux for 1.5 hr. It was then cooled down to r.t. and wasdiluted with Et₂O. The salts were filtered and the solvent wasevaporated. The residue was distilled bulb to bulb to obtain the titlecompound as a clear oil (305 mg).

NMR (¹H,): δ 3.96 (m, 1H), 3.5-3.4 (m, 4H), 3.39 (s, 6H), 2.2 (bs, 1H).

Intermediate 15

1-Trityloxy-butan-2-ol

To a solution of 1,2-butandiol (2 g) in anh. pyridine (15 mL) was addedtriphenylmethyl chloride (8 g). The dark reaction mixture was heated at100° C. for 8 hr and stirred at r.t. for 18 hr. The mixture was thenpoured in EtOAc/H₂O, the phases were separated and the organic layer waswashed with sat. aq. NaCl and dried over Na₂SO₄. The solids werefiltered and the solvent evaporated. The residual pyiridine waseliminated by filtration through a pad of silica gel (cHex/EtOAc 8/2).The solvent was evaporated and the residue was purified by flashchromatography (silica gel, cHex/EtOAc 95:5) to give the title compound(2.67 g)

NMR (¹H, CDCl₃): δ 7.42 (m, 6H),7.2 (m, 9H), 3.67 (q, 1H), 3.18 (q, 1H),3 (q, 1H), 2.6 (d, 1H), 1.42 (q, 2H), 0.85 (t, 3H).

MS (m/z): [MH]⁺.

Intermediate 16

7-(2,4-Dichloro-phenyl)-2-ethyl-4-(1-trityloxymethyl-propoxy)-6,7dihydro-5H-pyrrolo[2,3-d]pyrimidine

To a solution of intermediate 15 (180 mg) in anh. N-methylpyrrolidone (1mL), at r.t., under N₂, was added NaH 80%/oil (17 mg) and the reactionmixture was stirred at r.t. for 30 min. Intermediate 8 (85 mg) was thenadded and the reaction mixture was heated at 100° C. (screw cap vial)for 8 hr. It was then cooled down to r.t. and poured into CH₂Cl₂/H₂O.The phases were separated, the aqueous layer was extracted with CH₂Cl₂(2×10 mL) and the combined organic extracts were dried over Na₂SO₄. Thesolids were filtered and the solvent evaporated to dryness in vacuo. Theresidue was purified by flash chromatography (silica gel cHex/EtOAc 9:1)to give the title compound as a clear oil (50 mg).

NMR (¹H): δ 7.7-7.2 (m, 18H), 5.5 (r, 1H), 3.96 (t, 2H), 3.3 (q, 1H),3.15 (q, 1H), 3.05 (t, 2H), 2.4 (s, 3H), 1.65 (m, 2H), 0.8 (t, 3H).

MS (m/z): [MH]⁺610.

Intermediate 17

1-Trityloxy-butan-2-ol

To a solution of 1,2-butandiol (2 g) in anh. pyridine (15 mL) was addedtriphenylmethyl chloride (8 g). The dark reaction mixture was heated at100° C. for 8 hr and stirred at r.t. for 18 hr. The mixture was thenpoured in EtOAc/H₂O, the phases were separated and the organic layer waswashed with sat. aq. NaCl and dried over Na₂SO₄. The solids werefiltered and the solvent evaporated. The residual pyiridine waseliminated by filtration through a pad of silica gel (cHex/EtOAc 8:2).The solvent was evaporated and the residue was purified by flashchromatography (silica gel, cHex/EtOAc 95:5) to give the title compoundas a yellow oil (2.67 g).

NMR (¹H, CDCl₃): δ 7.42 (m, 6H),7.2 (m, 9H), 3.67 (q, 1H), 3.18 (q, 1H),3 (q, 1H), 2.6 (d, 1H), 1.42 (q, 2H), 0.85 (t, 3H).

MS (m/z): 332[MH]⁺.

Intermediate 18

7-(2,4-Dichloro-phenyl)-2-methyl-4-(1-trityloxymethyl-propoxy)-6,7-dihydro-5H-pyrrolo[2,3p]pyrimidine

To a solution of intermediate 17 (180 mg) in anh. N-methylpyrrolidone (1ml), at r.t., under N₂, was added NaH 80%/oil (17 mg) and the reactionmixture was stirred at r.t. for 30 min. Intermediate 8 (85 mg) was thenadded and the reaction mixture was heated at 100° C. (screw cap vial)for 8 hr. It was then cooled down to r.t. and poured into CH₂Cl₂/H₂O.The phases were separated, the aqueous layer was extracted withCH₂Cl₂(2×10 mL) and the combined organic extracts were dried overNa₂SO₄. The solids were filtered and the solvent evaporated to drynessin vacuo. The residue was purified by flash chromatography (silica gelcHex/EtOAc 9:1) to give the title compound as a clear oil (50 mg).

NMR (¹H,CDCl₃): δ 7.7-7.2 (m, 18H), 5.5 (m, 1H), 3.96 (t, 2H), 3.3 (q,1H), 3.15 (q, 1H), 3.05 (t, 2H), 2.4 (s, 3H), 1.65 (m, 2H), 0.8 (t, 3H)

MS (m/z): 610[MH]⁺

Intermediate 19

2-[7-(2,4-Dichloro-phenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-butan-1-ol

A solution of intermediate 18 (8 mg) in EtOH (1 mL) and TFA (0.5 mL) wasstirred at r.t. for 48 hr. The solvents were then evaporated, theresidue taken up in CH₂Cl₂ and washed with H₂O (3×10 mL) to eliminatethe residual acid. The organic layer was dried over Na₂SO₄, the solidswere filtered and the solvent evaporated. The crude compound waspurified by flash chromatography (silica gel cHex/EtOAc 9:1→8:2) to givethe title compound (5 mg) as a clear oil.

MS (m/z): 368 [MH]⁺.

NMR (¹H, DMSO-d₆): d 7.46 (d, 1H), 7.33 (d, 1H), 7.28 (dd, 1H), 4.87 (m,1H), 3.99 (m, 2H), 3.85 (m, 2H), 3.09 (m, 2H), 2.38 (s, 3H), 1.69 (m,2H), 1.03 (t, 3H).

Intermediate 20

(4.6-Dichloro-2-methl-pyrimidin-5-yl)acetic acid methyl ester

Sodium (1.74 g, 3 eq) was added portionwise to anh. MeOH (60 mL), at 0°C., under N₂. After consumption of metallic sodium, acetamidinehydrochloride (7.06 g, 3 eq) was added. After 20 min. of stirring theprecipitated NaCl was filtered off. A solution of2-ethoxycarbonyl-succinic acid diethyl ester (6.04 g, 24.5 mmol) inanhydrous CH₃OH (20 mL) was added to the solution of free acetamidineand the mixture was stirred at r.t. for 2 days. The reaction mixture wasconcentrated to dryness in vacuo and the yellow foam (8.69 g) obtainedwas then mixed with POCl₃ (6 eq) and CH₃CN (10 Vol.) and heated atreflux for 18 hours. The resulting solution was cooled to r.t. andpoured slowly into ice/water and conc. NH₄OH with vigorous stirring. Theproduct was extracted with EtOAc (3×). The combined organic extractswere washed with brine, dried over anh. Na₂SO₄, filtered andconcentrated in vacuo. The crude oil was purified by flashchromatography (silica gel, cHex/EtOAc 8:2). The title compound wasobtained as a yellow solid (98% in two steps)

NMR (¹H, CDCl₃): δ 5.85 (m, 1H), 5.15 (dq, 1H), 5.11 (dq, 1H), 3.61 (dt,2H), 2.67 (s, 3H).

MS (m/z): 202 [M]⁺ (2Cl).

Intermediate 21

2-(4,6-Dichloro-2-methyl-pyrimidin-5-yl)-ethanol

To a solution of intermediate 20 (4.0 g, 0.017 mol) in anh. TBF (60 mL),at −78° C., under N₂, was added DEBA1-H 1M/THF (52.5 mL, 3 eq) dropwise.After the addition was complete, the reaction mixture was stirred at−30° C. for 3 hr. A Rochelle salt solution was then added at 0° C. andthe phases were separated. The aqueous layer was extracted with EtOAc(2×50 mL) and the combined organic extracts were dried over anh. Na₂SO₄.The solids were filtered and the solvent evaporated. The title compoundwas obtained as a clear oil (3.1 gr, 89%) and was used in the next stepwithout further purification.

NMR (1H, CDCl₃): δ 4.90 (t, 2H), 3.15 (t, 2H), 2.64 (s, 3H), 1.70 (bs,1H).

MS (m/z): 207 [MH]⁺

Intermediate 22

5-[2-tert-Butyl-dimethyl-silanoxy)-ethyl]-4,6-dichloro-2-methyl-pyrimidine

To a solution of intermediate 21 (3.1 g, 0.015 mol) in anh. DMF (100mL), at 0° C., under N₂, were added imidazole (17 g, 17 eq),t-butyldimnethylsilyl chloride (6.35 gr, 2.8 eq) and DMAP (catalyticamount). The solution was stirred at r.t. for 18 hr. EtOAc (100 mL) andsat.aq. NH₄Cl (50 mL) were added and the phases were separated. Theorganic layer was washed with sat.aq. NaCl (2×100 mL) and dried overanh. Na₂SO₄. The solids were filtered and the solvent evaporated. Thecrude compound was purified by flash chromatography (silica gel,cHex/EtOAC 9:1) to give the title compound as a clear oil (4.6 g, 95%).

NMR (¹H, CDCl₃): δ 3.86 (t, 2H), 3.12 (t, 2H), 2.66 (s, 3H), 0.85 (s,9H), 0.01 (s, 6H).

MS (m/z): 321 [MH]⁺

Intermediate 23

(2,4-Bis-trifluoromethyl-phenyl)-{5-[2-(tert-butyl-dimethyl-silanoxy)-ethyl]-6-chloro-2-methyl-pyrimidin-4-yl}-amine

To a solution of 2,4-bis-trifluoromethyl-aniline (984 μL, 1 eq) in anh.DNF (15 mL), at 0° C., under N₂, was added NaH 80%/oil (400 mg, 2.2 eq).The reaction mixture was stirred at 0° C. for 30 min and was then addedto a solution of intermediate 22 (2 g, 6 mmol) in anh. DMF (15 mL) atr.t., under N₂. The reaction mixture was stirred at r.t. for 30 min. Theexcess NaH was carefully destroyed with sat.aq. NaCl and the reactionmixture was diluted with EtOAc. The phases were separated, the organiclayer was washed with sat.aq. NaCl (2×30 mL) and dried over anh. Na₂SO₄.The solids were filtered and the solvent evaporated. The crude compoundwas purified by flash chromatography (silica gel, cHex/EtOAc95:5→90:10).

The title compound was obtained as a clear oil (1.84 g, 56%).

NMR (¹H, CDCl₃): δ 8.61 (d, 1H), 8.04 (bs, 1H), 7.86 (s, 1H), 7.79 (d,1H), 4.95 (t, 2H), 3.95 (t, 2H), 2.53 (s, 3H), 0.73 (s, 9H), −0.90 (s,6H).

MS (m/z): 514 [MH]⁺

Intermediate 24

2-[4-(2,4-Bis-trifluromethy-phenylamino)-6-chloro-2-methyl-pyrimidin-5-yl]-ethanol

To a solution of intermediate 23 (1.84 g, 3.58 mmols) in anh. DMF (30mL), at r.t., under N₂, was added Et₃N.3HF (2.4 rn, 3 eq). The reactionmixture was stirred at r.t. for 18 hr. It was then diluted with coldsat.aq. NaCl (50 mL) and extracted with EtOAc (3×50 mL). The combinedorganic extracts were dried over anh. Na₂SO₄. The solids were filteredand the solvent evaporated. The title compound was obtained as a clearoil (1.4 gr, 98%) and was used in the next step without ftitherpurification.

NMR (¹H, CDCl₃): δ 8.59 (bs, 1H), 8.22 (d, 1H), 7.84 (s, 1H), 7.75 (d,1H), 4.06 (t, 2H), 3.01 (t, 2H), 2.50 (s, 3H)

MS (m/z): 400 [MH]⁺

Example 1 Synthesis of Representative Compounds of Structure (1a)

7-(2,4-Dichlorophenyl)-4-(1-ethyl-propoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]-pyrimidine(1-1)

To a suspension of NaH 80%/oil (4 mg) in anh. DMF (300 μL), at r.t.,under N₂, was added 3-pentanol (15.5 μL) and the reaction mixture washeated at 50° C. for 15-20 min, or until a clear orange solution wasobtained. Intermediate 8 (15 mg) was then added and the reaction mixturewas heated at 100° C. (screw cap vial) for 60 min. It was then cooleddown to r.t. and the solvent was evaporated. The residue was taken-up inH₂O and the aqueous layer was extracted with CH₂Cl₂ (3×10 mL). Thecombined organic extracts were dried over Na₂SO₄, the solids werefiltered and the solvent evaporated. The residue was purified by flashchromatography (silica gel, cHex/EtOAc 96:4) to obtain the titlecompound as a yellow oil (8 mg).

7-(2,4-Dichlorophenyl)-4-(1-isopropyl-2-methyl-propoxy)-2-methyl-6,7-dihydro-5H-pyrrolo-[2,3d]pyrimidine(1-2)

To a suspension of NaH 80%/oil (6 mg) in anh. DMF (0.5 mL), at r.t.,under N₂, was added 2,4 dimethyl-3-pentanol (20 μL). The reactionmixture was heated at 50° C. for 15-20 min, or until a clear orangesolution was obtained. Intermediate 8 (15 mg) was then added, and thereaction mixture was heated at 100° C. (screw cap vial) for 60 min. Itwas then cooled down to r.t. and poured in EtOAc/sat. aq. NaCl. Thephases were separated and the organic layer was further washed withsat.aq. NaCl (2×10 mL) and dried over Na₂SO₄. The solids were filteredand the solvent was evaporated. The crude product was purified by flashchromatography (silica gel, cHex/EtOAc 95:5) to yield the title compoundas a clear oil (9 mg)

7-(2,4-Dichlorophenyl)-4-isopropyl-3-methyl-butoxy)-2-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d]primidine(1-3)

To a suspension of NaH 80%/oil (4 mg) in anh. DMF (300 μL), at r.t.,under N₂, was added 2,5-dimethyl-3-hexanol (18.6 mg) and the reactionmixture was heated at 50° C. for 15-20 min, or until a clear solutionwas obtained. Intermediate 8 (15 mg) was then added and the reactionmixture was heated at 100° C. (screw cap vial) for 60 min. It was thencooled down to r.t. and the solvent was evaporated. The residue wastaken-up in H₂O and the aqueous layer was extracted with CH₂Cl₂ (3×10mL). The combined organic extracts were dried over Na₂SO₄, the solidswere filtered and the solvent evaporated. The residue was purified byflash chromatography (silica gel, cHex/EtOAc 96:4) two times to obtainthe title compound as a clear oil (2 mg).

7-(2,4-Dichlorophenyl)-4-(2-methoxy-1-methoxymethyl-ethoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3d]pyrimidine(1-4)

To a suspension of NaH 80%/oil (5.5 mg) in anh. DMF (300 μL), at r.t.,under N₂, was added intermediate 14 (20 mg) and the reaction mixture washeated at 50° C. for 15-20 min, or until a clear solution was obtained.Intermediate 8 (20 mg) was then added and the reaction mixture washeated at 100° C. (screw cap vial) for 60 min. It was then cooled downto r.t. and the solvent was evaporated. The residue was taken-up in H₂Oand the aqueous layer was extracted with CH₂Cl₂ (3×10 mL). The combinedorganic extracts were dried over Na₂SO₄, the solids were filtered andthe solvent evaporated. The residue was purified by flash chromatography(silica gel, cHex/EtOAc 96:4, then Tol/EtOAc 8:2) to obtain the titlecompound as a yellow oil (15.5 mg).

7-(2,4-Dichlorophenyl)4-(2-ethyl-butoxy)-2methyl-6,7-dihydro-5H-pyrrolo[2,3-d]-pyrimidine(1-5)

To a solution of intermediate 8 (10 mg) in 2-ethyl-1-butanol (100 μL),at r.t., under N₂, was added NaH 80%/oil (10 mg). The reaction mixturewas stirred at r.t. for 10 min, then heated at 60° C. for 15 hr. It wasthen cooled down to r.t. and poured in CH₂Cl₂/H₂O. The phases wereseparated and the organic layer was dried over Na₂SO₄. The solids werefiltered and the solvent was evaporated to yield the title compound as awhite foam (12 mg).

7-(2,4-Dichlorophenyl)-4-(2-ethoxy-1-ethoxymethyl-ethoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3d]pyrimidine(1-6

To a suspension of NaH 80%/oil (4.0 mg) in anh. DMF (300 μl) at r.t.,under N₂, was added 1,3-diethoxy-2-propanol (22.0 μl). The reactionmixture was stirred at 80° C. for 30 min. Intermediate 8 (15 mg) wasthen added and the reaction mixture was heated at 110° C. (screw capvial) for 1 hr. It was then cooled down to r.t. and poured into EtOAc.The organic layer was washed with sat. aq. NaCl (3×10 mL) and dried overNa₂SO₄. The solids were filtered and the solvent evaporated. The crudeproduct was purified by flash chromatography (silica gel, CHex/EtOAc96:4) to give the title compound as a colourless oil (12.0 mg).

7-(2,4-Bis-trifluoromethyl-phenyl)4-(1-ethyl-propoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine(1-7)

To a suspension of NaH 80%/oil (4.8 mg) in anh. DMF (300 μl), at r.t.,under N₂, was added pentan-3-ol (17 μl). The reaction mixture wasstirred at 80° C. for 15 min. Intermediate 13 (20 mg) was then added andthe reaction mixture was heated at 110° C. (screw cap vial) for 1 h. Itwas then cooled down to r.t. and poured into EtOAc. The organic layerwas washed with sat. aq. NaCl (3×10 mL) and dried over Na₂SO₄. Thesolids were filtered and the solvent evaporated. The crude product waspurified by flash chromatography (silica gel, cHex/EtOAc 95:5) to givethe title compound as a pale yellow solid (13.2 mg).

Example 1-1-13, 1-1-14 and 1-1-15 were prepared analogously, except that2-trifluoromethyl-4-cyano-aniline,2-chloro-3-amino-6-trifluoromethyl-pyridine and2-cyano-4-trifluoromethyl-aniline were used respectively instead of2,4-bis-trifluoromethyl-aniline in the production of intermediate 23

7-(2,4-Dichlorophenyl)-4-(1-ethyl-5-methyl-allyloxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3d]pyrimidine (1-8)

To a suspension of NaH 80%/oil (4.0 mg) in anh. DMF (300 μl) at r.t.,under N₂, was added 2-methyl-1-penten-3-ol (15 mg). The reaction mixturewas stirred at 80° C. for 30 min. Intermediate 8 (15 mg) was then addedand the reaction mixture was heated at 110° C. (screw cap vial) for 1hr. It was then cooled down to r.t. and poured into EtOAc. The organiclayer was washed with sat. aq. NaCl (3×10 mL) and dried over Na₂SO₄. Thesolids were filtered and the solvent evaporated. The crude product waspurified by flash chromatography (silica gel, cHex/EtOAc 96:4) to givethe title compound as colourless oil (7 mg).

7(2,4-Dichlorophenyl)-4-(1-methoxymethyl-propoxy)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3d]pyrimidine(1-9)

To a suspension of NaH 80%/oil (4.0 mg) in anh. DMF (300 μl) at r.t.,under N₂, was added 1-methoxy-butan-2-ol (15 mg). The reaction mixturewas stirred at 80° C. for 30 min.

Intermediate 8 (15 mg) was then added and the reaction mixture washeated at 110° C. (screw cap vial) for 1 hr. It was then cooled down tor.t. and poured into EtOAc. The organic layer was washed with sat. aq.NaCl (3×10 nL) and dried over Na₂SO₄. The solids were filtered and thesolvent evaporated. The crude product was purified by flashchromatography (silica gel, cHex/EtOAc 9:1) to give the title compoundas a colourless oil (11 mg).

2-[7-(2,4-Dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yloxy]butan-1-ol(1-10)

A solution of intermediate 16 (8 mg) in EtOH (1 mL) and TFA (0.5 mL) wasstirred at r.t. for 48 hr. The solvents were then evaporated, theresidue taken up in CH₂Cl₂ and washed with H₂O (3×10 mL) to eliminatethe residual acid. The organic layer was dried over Na₂SO₄, the solidswere filtered and the solvent evaporated. The crude compound waspurified by flash chromatography (silica gel cHex/EtOAc 9:1→8:2) to givethe title compound (5 mg) as a clear oil.

2-[7-(2,4-Bis-trifluoromethyl-phenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-butan-1-ol(1-16) was prepared analogously, except that intermediate 13 was usedinstead of intermediate 8 in the preparation of intermediate 18.

7-(2.4-Dichlorophenyl)-2-methyl-4-(1-trifluoromethoxymethyl-propoxy)-6,7-dihydro-5H-pyrrolo[2,3d]pyrimidine (1-11)

To a solution of intermediate 19 (6 mg) in anh. TBE (1 mL), at r.t.,under N₂, was added NaH 80%/oil (8 mg) and the reaction mixture wasstirred at r.t. for 30 min, or until gas evolution ceased. A solution oftrifluoromethyliodine 1.0M in TIF (3 mL) was then added and the reactionmixture was stirred at r.t. (screw cap vial) for 24 hr. It was thenpoured into CH₂Cl₂/NH₄Cl and the phases were separated. The aqueouslayer was further extracted with CH₂Cl₂ (2×10 mL) and the combinedorganic extracts were dried over Na₂SO₄. The solids were filtered andthe solvent evaporated to give the title compound still contaminatedwith the starting material.

Further representative compounds of this invention were prepared by theprocedure set forth in the above examples.

All the analytical data are set forth in the following Table 1. TABLE 1Cpd. N°. R R₁ R₂- Analytical Data 1-1 2,4-dichlorophenyl CH₃

NMR (¹H, CDCl₃): δ 7.46 (d, 1H), 7.38, (d, 1H), 7.26 (dd, 1H), 5.18 (m,1H), 3.96 (t, 2H), 3.04 (t, 2H), 2.39 (s, 3H), 1.69, (m, 4H), 0.94 (t,6H). MS (m/z): 366 [MH]⁺ 2 Cl. 1-2 2,4-dichlorophenyl CH₃

NMR (¹H, CDCl₃): δ 7.46 (d, 1H), 7.40 (d, 1H), 7.27 (dd, 1H), 5.16 (t,1H), 3.96 (t, 2H), 3.05 (t, 2H), 2.37 (s, 3H), 2.00 (m, 2H), 0.93 (t,12H). MS (m/z): 394 [MH]⁺ 2 Cl. 1-3 2,4-dichlorophenyl CH₃

NMR (¹H, CDCl₃): δ 7.51 (bs, 1H), 7.38 (d, 1H), 7.33 (bd, 1H), 5.39 (m,1H), 4.03 (bt, 2H), 3.11 (t, 2H), 2.58 (bs, 3H), 1.95, m, 1H), 1.68-1.55(m, 2H), 1.35 (m, 1H), 0.95 (m, 12H). MS (m/z): 408 [MH]⁺ 2 Cl. 1-42,4-dichlorophenyl CH₃

NMR (¹H,): δ 7.47 (d, 1H), 7.35 (d, 1H), 7.28 (dd, 1H), 5.64 (m, 1H),3.97 (t, 2H), 3.68 (m, 4H), 3.41 (s, 3H), 3.40 (s, 3H), 3.10 (t, 2H),2.43 (s, 3H). MS (m/z): 398 [MH]⁺ 2 Cl. 1-5 2,4-dichlorophenyl CH₃

NMR (¹H,): δ 7.46 (d, 1H), 7.37 (d, 1H), 7.27 (dd, 1H), 4.29 (d, 2H),3.96 (t, 2H), 3.06 (t, 2H), 2.41 (s, 3H), 1.7-1.6 (m, 1H), 1.5-1.4 (m,4H), 0.95 (t, 6H). MS (m/z): 380 [MH]⁺ 2 Cl. 1-6 2,4-dichlorophenyl CH₃

NMR (¹H, CDCl₃): δ 7.42 (d, 1H), 7.31 (d, 1H), 7.23 (dd, 1H), 5.54 (m,1H), 3.92 (t, 2H), 3.68 (d, 4H), 3.55 (m, 4H), 3.04 (t, 2H), 2.35 (s,3H), 1.17 (t, 6H). MS (m/z): 426 [MH]⁺. 1-7 2,4-bis-trifluoro-methyl-phenyl CH₃

NMR (¹H, CDCl₃): δ 8.01 (s, 1H), 7.88 (d, 1H), 7.57 (d, 1H), 5.25 (bs,1H), 3.97 (t, 2H), 3.10 (t, 2H), 2.46 (bs, 3H), 1.71 (m, 4H), 0.96 (t,6H). MS (m/z): 434 [MH]⁺. 1-8 2,4-dichlorophenyl CH₃

NMR (¹H, CDCl₃): δ 7.46 (d, 1H), 7.36 (d, 1H), 7.28 (dd, 1H), 5.58 (bs,1H), 5.02 (s, 1H), 4.91 (s, 1H), 3.98 (m, 2H), 3.08 (m, 2H), 2.41 (bs,3H), 1.81 (m, 2H), 1.78 (s, 3H), 0.95 (t, 3H). MS (m/z): 378 [MH]⁺. 1-92,4-dichlorophenyl CH₃

NMR (¹H, CDCl₃): δ 7.46 (d, 1H), 7.36 (d, 1H), 7.28 (dd, 1H), 5.43 (m,1H), 3.98 (m, 2H), 3.62 (dd, 1H), 3.56 (dd, 1H), 3.41 (s, 3H), 3.08 (m,2H), 2.42 (s, 3H), 1.75 (m, 2H), 0.98 (t, 3H). MS (m/z): 382 [MH]⁺. 1-102,4-dichlorophenyl CH₃

NMR (¹H, CDCl₃): δ 7.49 (t, 1H), 7.33 (t, 1H), 7.33 (s, 1H), 7.30 (d,1H), 4.9 (m, 1H), 4.42 (m, 1H), 4.01 (t, 2H), 3.84 (m, 1H), 3.80 (m,1H), 3.09 (t, 2H), 2.40 (s, 3H), 1.70 (m, 2H), 1.04 (t, 3H). MS (m/z):368 [MH]⁺ 2 Cl. 1-11 2,4-dichlorophenyl CH₃

MS (m/z): 438 [MH]⁺. 1-12 2,4-bistrifluoro- methylphenyl CH₃

NMR (¹H, CDCl₃): δ 7.99 (d, 1H), 7.86 (dd, 1H), 7.54 (d, 1H), 4.51 (dd,1H), 4.37 (dd, 1H), 3.92 (t, 2H), 3.49 (s, 3H), 3.45 (m, 1H), 3.10 (t,2H), 2.38 (s, 3H), 1.66 (m, 2H), 1.01 (t, 3H). MS (m/z): 450 [MH]⁺. 1-132-trifluoromethyl-4- carboxyamino-phenyl CH₃

NMR (¹H, CDCl₃): δ 8.19 (d, 1H), 8.00 (dd, 1H), 7.48 (d, 1H), 6.5-6.3(bs, 1H), 5.7-5.5 (bs, 1H), 5.19 (m, 1H), 3.91 (t, 2H), 3.06 (t, 2H),2.37 (s, 3H), 1.70 (m, 4H), 0.95 (t, 6H). 1-14 3-(2-(1-ethyl-propoxy)-6-trifluoro- methyl)-pyridine CH₃

NMR (¹H, CDCl₃): δ 8.20 (d, 1H), 7.41 (d, 1H), 5.93 (m, 2H), 4.20 (t,2H), 3.05 (t, 2H), 2.32 (s, 3H), 1.80-1.65 (m, 8H), 0.96-0.90 (m, 12H).MS (m/z): 453 [MH]⁺. 1-15 2-cyano-4-trifluoro- methyl-phenyl CH₃

NMR (¹H, CDCl₃): δ 7.92 (d, 1H), 7.88 (d, 1H), 7.75 (dd, 1H), 5.21 (m,1H), 4.33 (t, 2H), 3.08 (t, 2H), 2.47 (s, 3H), 1.69 (m, 4H), 0.93 (t,6H). IR (CDCl₃, cm⁻¹): 2228, 1590. 1-16 2,4-bistrifluoro- methyiphenylCH₃

NMR (¹H, CDCl₃): δ 8.01 (bs, 1H), 7.88 (d, 1H), 7.32 (d, 1H), 4.48-4.38(m, 2H), 3.95 (t, 2H), 3.84 (m, 1H), 3.12 (t, 2H), 2.35 (s, 3H), 1.60(m, 2H), 1.04 (t, 3H) IR (nujol, cm⁻¹): 3393 MS (m/z): 436 [MH]⁺.

Example 2 CRF Binding Activity

CRF binding affinity has been determined in vitro by the compounds'ability to displace ¹²⁵I-oCRF and ¹²⁵I-Sauvagine for CRF1 and CRF2 SPA,respectively, from recombinant human CRF receptors expressed in ChineseHamster Ovary (CHO) cell membranes. For membrane preparation, CHO cellsfrom confluent T-flasks were collected in SPA buffer (HEPES/KOH 50 mM,EDTA 2 mM; MgCl₂ 10 mM, pH 7.4.) in 50 mL centrifuge tubes, homogenizedwith a Polytron and centrifuged (50'000 g for 5 min at 4° C.: Beckmancentrifuge with JA20 rotor). The pellet was resuspended, homogenized andcentrifuged as before.

The SPA experiment has been carried out in Optiplate by the addition of100 μL the reagent mixture to 1 μL of compound dilution (100% DMSOsolution) per well. The assay mixture was prepared by mixing SPA buffer,WGA SPA beads (2.5 mg/mL), BSA (1 mg/mL) and membranes (50 and 5 μg ofprotein/mL for CRF1 and CRF2 respectively) and 50 PM of radioligand.

The plate was incubated overnight (>18 hrs) at room temperature and readwith the Packard Topcount with a WGA-SPA ¹²⁵I counting protocol.

Example 3 CRF Functional Assay

Compounds of the invention were characterised in a functional assay forthe determination of their inhibitory effect. Human CRF—CHO cells werestimulated with CRF and the receptor activation was evaluated bymeasuring the accumulation of cAMP.

CHO cells from a confluent T-flask were resuspended with culture mediumwithout G418 and dispensed in a 96-well plate, 25'000 c/well, 100μL/well and incubated overnight. After the incubation the medium wasreplaced with 100 μL of cAMP IBMX buffer warmed at 37° C. (5 mM KCl, 5mM NaHCO₃, 154 mM NaCl, 5 mM HEPES, 2.3 mM CaCl₂, 1 mM MgCl₂; 1 g/Lglucose, pH 7.4 additioned by 1 mg/mL BSA and 1 mM IBMX) and 1 μL ofantagonist dilution in neat DMSO. After 10 additional minutes ofincubation at 37° C. in a plate incubator without CO₂, 1 μL of agonistdilution in neat DMSO was added. As before, the plate was incubated for10 minutes and then cAMP cellular content was measured by using theAmersham RPA 538 kit.

Example 4 General Method for Radiolabelling the Compounds of Formula (I)

Materials and Methods

Unless otherwise stated reagents may be obtained in analytical gradefrom commercial sources (Aldrich, Fluka, BDH, Phoenix, etc.) and may beused without carying fuiher purification.

Quality control of [¹¹C]derivatives may be performed on a Gilson highperformance liquid chromatography (HPLC) system (305-307 pumps, 118UVdetector) connected with a Bioscan FlowCount. Data analyses of thechromatograms were carried out with Laura 3 software (LabLogic SystemsLimited).

Radiolabelling

Synthesis of [¹¹C]methyl iodide.

The production of [¹¹C]CO₂ via the ¹⁴N(p,α)¹¹C reaction may be carriedout by irradiation of a nitrogen target (N₂, 99.99%) with 0.5% O₂(99.99%) at a 17 MeV cyclotron (General Electric PET-trace). [¹¹C]CH₃Imay be prepared by catalytic reduction (Ni) of [¹¹]CO₂ to [¹¹C]CH₄followed by gas phase iodination with I₂ using the PETtrace MeI MicroLabsystem(General Electric).

Example 5 Radiolabelling by [¹¹C]methylation of compounds (I)

[¹¹C]methyliodide may be passed through a reaction mixture containingthe corresponding desmethyl precursor (0.7 mg) and an organic orinorganic base in dimethylformamide (100 μl) contained in a glass or astainless steel container at room temperature for 2.5 min. Aftertrapping, the reaction mixture may be heated at 85° C. for 10 min andinjected onto a semi-preparative column for purification.Semi-preparative and analytical reverse phase HPLC columns were used forpurification and quality control of the radioligand. The UV-detectionwavelengths may be 254 nm for the semi-preparative HPLC and 254 nm forthe analytical HPLC. [¹¹C](1-9) and [¹¹C](1-12) may be chromatographedon a Waters C18 Column (μ-Bondapak, 10μ, 300×7.8 mm).

Using 50% acetonitrile in 70 mM phosphate buffer as mobile phase at flowrate of 8 ml/min, [the final compouns may be eluted and fractionated.

The product fraction may be collected was evaporated to dryness, andreformulated in 0.9% NaCl. Sterile filtration of the product through aMillipore filter (Millex®-GS, 0.22 μm pore size) into a 11 ml evacuatedsterile vial (Mallinckrodt) may provid a final product suitable forhuman use.

The radiochemical yields of the labeled compound varied between 40 and50% corrected for decay with reference to iodomethane.

Quality controls may be performed on a Sphericlone column (ODS 250×4.6mm). Using 50% Ethanol in 70 mM NaH₂PO₄ as mobile phase at flow rate of1.5 ml/min, the final compouns may be eluted.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described herein above.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1. Compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof

wherein R is aryl or heteroaryl and each of the above groups R may be substituted by 1 to 4 groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —COR₄, nitro, —NR₃R₄ cyano, or a group R₅; R₁ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR₃R₄ or cyano; R₂ corresponds to a group CHR₆R₇; R₃ is hydrogen, C1-C6 alkyl; R₄ independently from R₃, has the same meanings; R₅ is C₃-C₇ cycloalkyl, which may contain one or more double bonds; aryl; or a 5-6 membered heterocycle; wherein each of the above groups R₅ may be substituted by one or more groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, C1-C6 dialkylamino, nitro or cyano; R₆ is hydrogen, C2-C6 alkenyl or C1-C6 alkyl, wherein each of the above groups R₆ may be substituted by one or more groups selected from: C1-C6 alkoxy and hydroxy; R₇ independently from R₆, has the same meanings; X is carbon or nitrogen.
 2. Compounds, according to claim 1, of general formula (Ia)

in which R, R₁, and R₂ are defined as in claim
 1. 3. Compounds, according to claim 1, of general formula (Ib)

in which R, R₁, and R₂ are defined as in claim
 1. 4. Compounds, according to claim 1, wherein R₁ is C1-C3 alkyl group or halo C1-C3 alkyl group.
 5. Compounds, according to claim 1, wherein R is an aryl group selected from: 2,4-dichlorophenyl, 2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethyl, 2-chloro-4-methoxyphenyl, 2,4-dimethylphenyl, 2-methyl-4-methoxyphenyl, 2-methyl-4-chlorophenyl, 2-methyl-4-trifluoromethyl, 2,4-dimethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-methylphenyl, 2-trifluoromethyl-4-chlorophenyl, 2,4-trifluoromethylphenyl, 2-trifluoromethyl-4-methylphenyl, 2-trifluoromethyl-4-methoxyphenyl, 2-bromo-4-isopropylphenyl, 4-methyl-6-dimethylaminopyridin-3-yl, 3,5-dichloro-pyridin-2-yl, 2,6-bismethoxy-pyridin-3-yl and 3-chloro-5-tricloromethyl-pyridin-2-yl.
 6. A compound, according to claim 1, selected in a group consisting from:
 7. A process for the preparation of a compound of formula (I) as claimed in claim 1, which comprises the reaction of a compound of formula (II), wherein L is a leaving group,

with the alcohol compound (III) HOCHR_(2a)R_(3a) wherein R_(2a) and R_(3a) have the meanings defined in claim 1 for R₂ and R₃ or are a group convertible thereto. 8-14. (Cancelled).
 15. A pharmaceutical composition comprising a compound according to claim 1, in admixture with one or more physiologically acceptable carriers or excipients.
 16. A diagnostic formulation comprising a radiolabelled compound according to claim 1, in admixture with one or more physiologically acceptable carriers or excipients.
 17. A method for the treatment of a mammal, including man, in particular in the treatment of conditions mediated by CRF (corticotropin-releasing factor), comprising administration of an effective amount of a compound according to claim
 1. 18. A method, according to claim 17, in the treatment of depression and anxiety, comprising administration of an effective amount of a compound according to claim
 1. 19. A method, according to claim 17, in the treatment of IBS (irritable bowel disease) and IBD (inflammatory bowel disease), comprising administration of an effective amount of a compound according to claim
 1. 20. A method for the diagnosis of conditions mediated by CRF (corticotropin-releasing factor) in an animal, including man, comprising administration of an effective amount of a radiolabelled compound according to claim
 1. 